Douglas O. Spry

Structure-activity relationship of carbacephalosporins and cephalosporins: antibacterial activity and interaction with the intestinal proton-dependent dipeptide transport carrier of Caco-2 cells.

An intestinal proton-dependent peptide transporter located on the lumenal surface of the enterocyte is responsible for the uptake of many orally absorbed beta-lactam antibiotics. Both cephalexin and loracarbef are transported by this mechanism into the human intestinal Caco-2 cell line. Forty-seven analogs of the carbacephalosporin loracarbef and the cephalosporin cephalexin were prepared to evaluate the structural features necessary for uptake by this transport carrier. Compounds were evaluated for their antibacterial activities and for their ability to inhibit 1 mM cephalexin uptake and, subsequently, uptake into Caco-2 cells. Three clinically evaluated orally absorbed carbacephems were taken up by Caco-2 cells, consistent with their excellent bioavailability in humans. Although the carrier preferred the L stereoisomer, these compounds lacked antibacterial activity and were hydrolyzed intracellularly in Caco-2 cells. Compounds modified at the 3 position of cephalexin and loracarbef with a cyclopropyl or a trifluoromethyl group inhibited cephalexin uptake. Analogs with lipophilic groups on the primary amine of the side chain inhibited cephalexin uptake, retained activity against gram-positive bacteria but lost activity against gram-negative bacteria. Substitution of the phenylglycl side chain with phenylacetyl side chains gave similar results. Compounds which lacked an aromatic ring in the side chain inhibited cephalexin uptake but lost all antibacterial activity. Thus, the phenylglycl side chain is not absolutely required for uptake. Different structural features are required for antibacterial activity and for being a substrate of the transporter. Competition studies with cephalexin indicate that human intestinal Caco-2 cells may be a useful model system for initially guiding structure-activity relationships for the rational design of new oral agents.

S(1)-C(2)-secocephems

Abstract Preparation of acetylenic-S(1)-C(2)-secocephems from the reaction of Grignard reagents on cis -α-vinylhalo sulfoxides.

C(3)-azido cephem II

Abstract The major product from the thermolysis and photolysis of C(3)-azido cephem 2 is the ring expanded 1,4,6-thiadiazepine azetidinone.

C(2)-vinylhalo-cephems

Abstract C(2)-vinylhalo-cephems are prepared from a Pummerer type rearrangement of the corresponding sulfoxide with dimethyl immonium halide.

Approaches to the chemical synthesis of the prostaglandins

This is a detailed report of efforts to synthesize compounds related to PGE1 (prostaglandin E1). Basically the approach involved attaching 1 or both of the side chains to an appropriately substituted benzene ring and subsequently converting the aromatic nucleus to the cyclopentane system. The chemical structure in each step of the process is diagrammed.

Radical Rearrangement: A Strategy for Conversion of Cephalosporin to 1-Carba(dethia)cephalosporin

Abstract A radical rearrangement approach to semisynthesis of the carbacephem class of β-lactam antibiotics is reported. The crucial bond construction in assembly of the carbacephem framework was accomplished by intramolecular C–C bond formation between an azetidin-2-one-4-yl and a pendant diene ester. This reactive intermediate was generated by fragmentation of a cephem derived radical followed by loss of sulfur dioxide. The radical precursor was prepared in 63% yield over four steps and the subsequent rearrangement reaction provided carbacephem products in a single step at 23% yield.

Rearrangement of exomethylenecephams to homocephams

Exomethylenecephans rearrange by reaction with diazo compounds in the presence of cupric sulfate to generaye the homocepham ring-system

Synthesis of oxa and dithiazepine azetidinones

Abstract Oxa and dithiazepine azetidinones are prepared from the versatile halomethyl sulfide intermediate 5 .

The [2,3]sigmatropic rearrangement of sulfilimines from 3-exomethylenecephams

-3-Exomethylenecepham sulfides react with phthalimidonitrene and the resulting sulfilimine undergoes a [2,3] sigmatropic rearrangement to give the 1,2,6-thiadiazepine azetidinone ring system

Rearrangement of benzothiazine sulphoxides

The reaction of substituted benzothiazine sulphoxides with Ac2O under reflux leads by an elimination reaction to a sulphenic acid derivative which undergoes subsequent addition to the generated double bond if the nitrogen is tertiary but is trapped as a cyclic sulphenamide by a secondary nitrogen.